ABSTRACT Primary forms of autonomic failure (AF) are rare neurodegenerative disorders characterized by loss of neural pathways responsible for the regulation of blood pressure. The clinical hallmark is orthostatic hypotension, which is a cause of disability, and a risk factor for falls and mortality. Paradoxically, a significant number of AF patients also have severe supine hypertension, which can be associated with end-organ damage and, though pressure diuresis, can worsen orthostatic hypotension. The arterial circulation has been the focus in the understanding and treatment of orthostatic hypotension in AF; the only available treatments for this condition are pressor agents designed to increase vascular resistance. Less attention has been given to venous capacitance, in particular in the splanchnic region. Our preliminary studies indicate that the main reason blood pressure falls when AF patients stand is a profound decrease in stroke volume and cardiac output, indicative of inappropriate venous pooling. Contraction of the splanchnic circulation, driven by residual sympathetic tone, also appears to play a role in supine hypertension in these patients. In Specific Aim 1 we propose to test the hypothesis that a reduction in splanchnic capacitance contributes to supine hypertension in autonomic failure. In specific Aim 2 we will determine the effects of midodrine and droxidopa, the only approved treatments for neurogenic orthostatic hypotension, on splanchnic capacitance. Focusing on interventions that improve venous return, rather than only peripheral arterial constriction, would represent a paradigm shift in how we treat these patients. That splanchnic capacitance contributes to the regulation of blood pressure is not a new concept, and its importance has recently been highlighted by results of animal studies. The clinical translation of these findings to humans has lagged behind because of limitations in previous experimental approaches. We believe we have the right patient population (primary autonomic failure), an effective intervention to gauge autonomic contribution to hypertension (the ganglionic blocker trimethaphan), and appropriate methods (segmental impedance) to overcome these limitations and study the contribution of the splanchnic circulation to blood pressure regulation in humans.